Psychotherapy remains a cornerstone of treatment for many psychiatric disorders, and can be highly effective for a portion of patients. Very little, however, is understood about the neurobiological mechanisms of action of psychotherapy, nor are there biological markers for who is likely to respond. For some disorders, such as posttraumatic stress disorder (PTSD), psychotherapy is also the only evidence-based treatment, leaving non-responders with no effective treatment alternative. A lot is known, by contrast, about the neural basis of PTSD. Despite this, there is a large gap between our understanding of the neural basis of psychopathology in PTSD and the mechanisms of therapeutic change, and an even larger gap between those and an ability to use information from neuroimaging studies to guide the development of novel, neurocircuitry-targeting treatments. This latter issue is one, in fact, that plagues neuroimaging studies of psychiatric disorders more generally. Development of such novel treatments is a major goal of the Strategic Plan of the NIMH, and thus the BRAINS RFA, and may bring new hope to the treatment of severe illnesses, such as PTSD. The overall goal of this research program is to apply functional magnetic resonance imaging (fMRI) to elucidate the brain circuitry underlying improvement in response to psychotherapy, and to leverage this knowledge to develop a novel, personalized, neurocircuitry- targeting treatment using transcranial magnetic stimulation (TMS). One potential mechanism of action of psychotherapy is the alteration of patterns of dysfunctional emotional processing. Numerous studies with healthy subjects has delineated the neural circuitry for reacting to and regulating negative emotion, and how it is perturbed in psychopathology. We propose to build on this knowledge and study psychotherapeutic change and its pretreatment predictors by systematically probing emotional reactivity and regulation using fMRI in patients with PTSD before and after treatment with prolonged exposure psychotherapy (PE), versus wait list. Before receiving PE, all patients will undergo mapping of the prefrontal cortex using concurrent TMS and fMRI. Patterns of brain activation induced and modulated by TMS at a variety of prefrontal sites will be compared to those associated with successful PE, thereby forming the basis for a future neuroimaging-guided TMS intervention strategy that is directly informed by an understanding of the neurocircuitry of treatment response. A successful outcome in this study may therefore produce a paradigm shift in the translation of clinical neuroscience to brain circuit- based interventions. PUBLIC HEALTH RELEVANCE: Psychotherapy is a commonly-used clinical tool in psychiatry and can be highly effective, but very little is currently known about either its mechanisms of action in the brain, or markers of who will or will not respond to psychotherapy. Moreover, for disorders such as posttraumatic stress disorder (PTSD), the only evidence-based effective treatment is psychotherapy, leaving therapy non-responders without an alternative effective treatment. The overall goal of this research program is therefore to use neuroimaging to elucidate changes in the brain circuitry underlying improvement with a specific form of psychotherapy for PTSD, and to leverage this knowledge to develop a novel, personalized, brain circuitry-guided treatment using non-invasive brain stimulation.